Orthopoxvirus is a genus of the Poxviridae family of complex DNA viruses that replicate in the cytoplasm of vertebrate and invertebrate cells. The Poxviridae family is characterized by having a large complex virion containing enzymes that synthesize mRNA, a genome composed of a single linear double-stranded DNA molecule of 130-300 kilobase pairs with a hairpin loop at each end, and a cytoplasmic site of replication. Members of the orthopoxvirus genus include cowpox, monkeypox, vaccinia, and variola virus [for a description of the Poxviridae family, reference is made to B. Moss, “Poxviridae: The Viruses and Their Replication,” in Fields Virology, B. N. Fields, et al., Eds., 3rd ed., Ch. 83, pages 2637-2671 (1996)]. Variola virus is the agent responsible for smallpox infections. Smallpox infections were effectively eradicated subsequent to the introduction of prophylactic vaccinations with cowpox and vaccinia virus. However, most of the human populations worldwide are no longer immune to smallpox as a result of the discontinuation of routine vacination in the early 1980's.
There are very few compounds available as therapeutics against orthopoxvirus infections. Two drugs under investigation are cidofovir and ribavirin. Cidofovir is the generic name for (S)-1-[3-hydroxy-2-(phosphonylmethoxy)-propyl]cytosine [(S)-HPMPC] which is currently the leading agent for the treatment of orthopoxvirus infections in humans. It is potent against vaccinia and cowpox virus infection in mice when administered subcutaneously or intraperitoneally. However, cidofovir's therapeutic utility is limited by safety concerns as well as lack of oral bioavailablity [see D. F. Smee et al., “Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice,” Antiviral Res., 52: 55-62 (2001) and references cited therein]. Inhibition of vaccinia virus is considered in the art to be predictive of inhibitory activity against other orthopoxviruses, including variola; see E. De Clercq, “Vaccinia Virus Inhibitors as a Paradigm for the Chemotherapy of Poxvirus Infections,” Clin. Microbiol. Rev., 14: 382-397 (2001).
Ribavirin has also been found to inhibit vaccinia virus and other orthopoxvirus replication in cell culture (see J. H. Huffman et al., “In vitro effect of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide on DNA and RNA viruses,” Antimicrobial Agents and Chemotherapy, 3: 235-241 (1973) and D. F. Smee et al., “Potential of the IMP dehydrogenase inhibitors for antiviral therapies of poxvirus infections,” Antiviral Res., 37: A89 (1998)]. Ribavirin was also reported to suppress vaccinia virus-induced lesions in a mouse model and to effectively treat vaccinia keratitis in rabbits. However, ribavirin causes anemia during prolonged administration and at high doses has certain immunosuppressive properties limiting its clinical usefulness against orthopoxvirus.
Consequently, there exists a need for more effective anti-orthopoxvirus agents particularly as a result of the threat of either variola (smallpox) or monkeypox viruses in biowarfare or bioterrorism. Preferably such agents should be effective when administered orally and be safe and well-tolerated by the host.
It has now been found that nucleoside compounds of the present invention and certain derivatives thereof are potent inhibitors of orthopoxvirus replication and in particular of vaccinia, variola, cowpox, and monkeypox virus replication. The instant nucleoside compounds and derivatives thereof are useful to treat orthopoxvirus infection and in particular vaccinia, variola, cowpox, and monkeypox virus infection.
It is therefore an object of the present invention to provide nucleoside compounds and certain derivatives thereof which are useful as inhibitors of the replication of orthopoxvirus and in particular as inhibitors of the replication of vaccinia, variola, cowpox, and monkeypox virus.
It is another object of the present invention to provide nucleoside compounds and certain derivatives thereof which are useful in the treatment of orthopoxvirus infection and in particular in the treatment of vaccinia, variola, cowpox, and monkeypox virus infection.
It is another object of the present invention to provide pharmaceutical compositions comprising the nucleoside compounds of the present invention in association with a pharmaceutically acceptable carrier.
It is another object of the present invention to provide pharmaceutical compositions comprising the nucleoside compounds and derivatives of the present invention for use as inhibitors of orthopoxvirus replication and in particular as inhibitors of vaccinia, variola, cowpox, and monkeypox virus replication.
It is another object of the present invention to provide pharmaceutical compositions comprising the nucleoside compounds and derivatives of the present invention for use in the treatment of orthopoxvirus infection and in particular in the treatment of vaccinia, variola, cowpox, and monkeypox virus infection.
It is another object of the present invention to provide pharmaceutical compositions comprising the nucleoside compounds and derivatives of the present invention in combination with other agents active against orthopoxvirus and in particular against vaccinia, variola, cowpox, and monkeypox virus.
It is another object of the present invention to provide methods for the inhibition of orthopoxvirus replication and in particular for the inhibition of vaccinia, variola, cowpox, and monkeypox virus replication.
It is another object of the present invention to provide methods for the treatment of orthopoxvirus infection and in particular for the treatment of vaccinia, variola, cowpox, and monkeypox virus infection.
It is another object of the present invention to provide methods for the treatment of orthopoxvirus infection in combination with other agents active against orthopoxvirus and in particular for the treatment of vaccinia, variola, cowpox, and monkeypox virus infection in combination with other agents active against vaccinia, variola, cowpox, and monkeypox virus infection.
It is another object of the present invention to provide nucleoside compounds and certain derivatives thereof and their pharmaceutical compositions for use as a medicament for the inhibition of orthopoxvirus replication and/or the treatment of orthopoxvirus infection and in particular for the inhibition of vaccinia, variola, cowpox, and monkeypox virus replication and/or the treatment of vaccinia, variola, cowpox, and monkeypox virus infection.
It is another object of the present invention to provide for the use of the nucleoside compounds and certain derivatives thereof of the present invention and their pharmaceutical compositions for the manufacture of a medicament for the inhibition of orthopoxvirus replication and/or the treatment of orthopoxvirus infection and in particular for the inhibition of vaccinia, variola, cowpox, and monkeypox virus replication and/or the treatment of vaccinia, variola, cowpox, and monkeypox virus infection.
These and other objects will become readily apparent from the detailed description which follows.